The manufacturing method has an influence on the mixing capacity and phase behavior of solid dispersions. Heat pre-treatment of the solutions before spray-drying can result in a higher kinetic miscibility. Amorphization of the copolymer by spray-drying before using it as an excipient for hot-melt extrusion can be a manufacturing benefit.

den Mooter, Guy (2017) Controlling the release of indomethacin from glass solutions layered with a rate controlling membrane using fluid-bed processing. A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription. AbstractFluid bed coating has been shown to be an adequate manufacturing technique to formulate poorly soluble drugs in glass solutions. Layering inert carriers with a drug-polymer mixture enables these beads to be immediately filled into capsules, thus avoiding additional, potentially destabilizing, downstream processing. In this study fluid bed coating is proposed for the production of controlled release dosage forms of glass solutions by applying a second, rate controlling membrane on top of the glass solution. Adding a second coating layer adds to the physical and chemical complexity of the drug delivery system so a thorough understanding of the physical structure and phase behavior of the different coating layers is needed. This study aimed to investigate the surface and cross-sectional characteristics (employing SEM and ToF-SIMS) of an indomethacin-polyvinylpyrrolidone (PVP) glass solution, top-coated with a release rate controlling membrane consisting of either ethyl cellulose or Eudragit RL. The implications on the addition of a pore former (PVP) and the coating medium (ethanol or water) were also considered. In addition, polymer miscibility and the phase analysis of the underlying glass solution were investigated.Significant differences in surface and cross sectional topography of the different rate controlling membranes or the way they are applied (solution vs. dispersion) were observed. These observations can be linked to the polymer miscibility differences. The presence of PVP was observed in all rate controlling membranes, even if it is not part of the coating solution. This could be attributed to residual powder presence in the coating chamber. The distribution of PVP among the sample surfaces depends on the concentration and the rate controlling polymer used.Differences can again be linked to polymer miscibility. Finally, it was shown that the underlying glass solution layer remains amorphous after coating of the rate controlling membrane, whether formed from an ethanol solution or an aqueous dispersion.4

Fluid bed coating has been proposed in the past as an alternative technology for manufacturing of drug-polymer amorphous solid dispersions, or so-called glass solutions. It has the advantage of being a one-step process, and thus omitting separate drying steps, addition of excipients, or manipulation of the dosage form. In search of an adequate sample preparation method for modulated differential scanning calorimetry analysis of beads coated with glass solutions, glass transition broadening and decrease of the glass transition temperature (Tg ) were observed with increasing particle size of crushed coated beads and crushed isolated films of indomethacin (INDO) and polyvinylpyrrolidone (PVP). Substituting INDO with naproxen gave comparable results. When ketoconazole was probed or the solvent in INDO-PVP films was switched to dichloromethane (DCM) or a methanol-DCM mixture, two distinct Tg regions were observed. Small particle sizes had a glass transition in the high Tg region, and large particle sizes had a glass transition in the low Tg region. This particle size-dependent glass transition was ascribed to different residual solvent amounts in the bulk and at the surface of the particles. A correlation was observed between the deviation of the Tg from that calculated from the Gordon-Taylor equation and the amount of residual solvent at the Tg of particles with different sizes.

Enteric-coated fixed-dose combinations of ezetimibe and lovastatin were prepared by fluid bed coating aiming to avoid the acidic conversion of lovastatin to its hydroxyacid derivative. In a two-step process, sucrose beads were layered with a glass solution of ezetimibe, lovastatin and Soluplus, top-coated with an enteric layer. The impact of different bead size, enteric polymers (Eudragit L100 and Eudragit L100-55) and coating time was investigated. Samples were evaluated by X-ray diffraction, scanning electron microscopy, laser diffraction and in vitro studies in 0.1M HCl and phosphate buffer pH 6.8. Results showed that smaller beads tend to agglomerate and release was jeopardized in acidic conditions, most likely due to irregular coating layer. Eudragit L100-55 required longer processing, but thinner coating layers provided lower drug release. Both polymers showed low drug release in acidic environment and fast release at pH 6.8. The off-line measurement of the coating thickness determined the ideal coating time as 15 and 30min for Eudragit L100-55 and Eudragit L100-based samples, respectively. Both compounds were molecularly dispersed in Soluplus, and Eudragit L100 formulations showed concave pores on the surface, presenting higher drug release in acidic conditions. Stability studies after 6 months showed unaltered physical properties and drug release.

This study aimed to investigate the pharmaceutical performance of an indomethacin-polyvinylpyrrolidone (PVP) glass solution applied using fluid bed processing as a layer on inert sucrose spheres and subsequently top-coated with a release rate controlling membrane consisting of either ethyl cellulose or Eudragit RL. The implications of the addition of a pore former (PVP) and the coating medium (ethanol or water) on the diffusion and release behavior were also considered. In addition, the role of a charge interaction between drug and controlled release polymer on the release was investigated. Diffusion experiments pointed to the influence of pore former concentration, rate controlling polymer type, and coating solvent on the permeability of the controlled release membranes. This can be translated to drug release tests, which show the potential of diffusion tests as a preliminary screening test and that diffusion is the main factor influencing release. Drug release tests also showed the effect of coating layer thickness. A charge interaction between INDO and ERL was demonstrated, but this had no negative effect on drug release. The higher diffusion and release observed in ERL-based rate controlling membranes was explained by a higher hydrophilicity, compared to EC.